Methylsulfonylmethanesulfonic acid alkylene esters

ABSTRACT

A,W-BIS(METHYLSULFONYLMETHYLSULFONYLOXY)ALKANES HAVING UP TO AND INCLUDING 14 CARBON ATOMS IN THE ALKANE GROUP ARE CYTOSTATIC AGENTS. THE COMPOUNDS, OF WHICH 1,3-BIS(METHYLSULFONYLMETHYLSULFONYLOXY)PROPANE IS A REPRESENTATIVE EMBODIMENT, ARE PREPARED FROM A,W-DIIODOALKANE OF UP TO 14 CARBON ATOMS AND SILVER METHYLSULFONYLMETHANESULFONATE.

United States Patent" 3 so: 200 METHYLSULFONYLMETHANESULFONIC ACID ALKYLENE ESTERS Alexander Senning, Brabrand, Denmark, and Robert Bier- Patented Apr. 9, 1974 "ice 2CHr-SOz-CHz-COFAg I-(CH2)n III II ling, Wuppertal-Elberfeld, Dieter Steinholf, Bochurn, 5 and Gerhard Trossmann, B nn-B rg, The manufacture of the new compounds will be exmany, assigflol's Fal'benfabl'lkell Bayer Lever plained with the aid of the following examples: kusen, Germany No Drawing. Filed ept. 14, 1971, Ser. No. 180,496 Example 1 Clams Pnonty! g g z ggg g Sept 1970 A mixture of 22.48 g. of silver methylsulfonylmethane- Int. CL Con 14'1/02 sulfonate, 100 ml. of anhydrous acetonitrile and 14.64 g. Us. CL 260456 R 8 Claims of l,8-diiodooctane (II; n=8) is stirred for 7 hours at room temperature (about 22 C.) and is subsequently left to stand overnight. The silver iodide which separates ABSTRACT OF THE DISCLOSURE 15 out is filtered off, and the filtrate is concentrated in vacuo. ago-Bis(methylsulfonylmethylsulfonyloxy)alkanes hav- The residue is twice recrystallized from chlol'ofol'ming up to and including 14 carbon atoms in the alkane of methylsulfonylmethanesulfonic acid Octamethylene group are cytostatic agents. The compounds, of which alternatively named as Y Y l,3-bis(methylsulfonylmethylsulfonyloxy)propane is a ylsulfonyloxwoctane. of melting P0111t 89-91? an representative embodiment, are prepared from 0:,w-dithus Obtainediodoalkane of up to 14 carbon atoms and silver methyl- Silver methylsulfonylmethanesulfbnate is Obtained as su1f0ny1methane5u1fnate follows: 114.0 g. of methanesulfonyl chloride are added dropwise over the course of 30 minutes to a mixture of 210 ml. of triethylamine and 400 ml. of anh drous aceto DETAILED DESCRIPTION nitrile, at -40 0., while stirring. The mixt iire a stirred The present invention relates to novel aliphatic sulfonic further hour at and of Water are acid diesters, to their preparation, to their use as cytoadded. again at After a further 15 s static agents and to compositions adapted to that use. tiffing at the mixture is filtered and the filtrate In particular, the present invention pertains to is concentrated in vacuo. After adding 500 ml. of 2 N Pounds of the formula: sodium hydroxide, 60 g. of crystals of melting point 235- 240 C. are obtained, and these are filtered off. After re- CH -SO CH -SO -O(CH crystallization from ethanol/water, sodium methylsul- OSO CH SO 'CHa (I) fonylmethanesulfonate melts between 239 and 241 C. v 40 g. of sodium methylsulfonylmethanesulfonate are disgi g g zj 2 gigz gi g gg s fi of from 3 to 12. solved in 1 liter of water and the solution is passed through The new sulfonic acid esters are obtained if an ot,wexqhimger colilmn-wlth a Polystyiene Synthwc diiodoalkane of Formula II resin containing sulfonic acid groups as the ion exchanger.

The aqueous solution of the free methylsulfonylmethane- I-(CH I (II) 40 sulfonic acid is digested with 69 g. of silver carbonate, wherein n is as dfifined above whereupon 40 g. of silver carbonate remain undissolved and are filtered off. The filtrate is concentrated in vacuo, is allowed to react with about the stoichiometric amount with the bath temperature not exceeding 60 C. After of silver methylsulfonylmethanesulfonate at temperatures adding methanol, g. of crystalline silver methylsulin the range of from about to about 100 C-, fonylmethanesulfonate of melting point 186-190 C. are in the presence of an organic diluent. In the reaction, the 45 obtained. reactants are preferably employed in approximately the The following compounds are substituted for 1,8-distoichiometrically required amounts. iodooetane in the procedure of Example 1:

The reaction is carried out in the temperature range of from about --l00 to about 100 0., preferably at Example stamllg mammal about 20 to 30 0., preferably in the presence of an 2 ii organic diluent. Polar aprotic solvents, such as anhydrous 3 ii acetonitrile, are preferentially employed. 4 ii The diiodo compounds II which serve as the starting 5 ii compounds are known. Silver methylsulfonylmethanesul- 6 ii fonate which serves as the other starting compound can 7 lg'dugdononane' be manufactured from methanesulfonyl chloride through 8 ii the formation of sodium methylsulfonylmethanesulfonate. 9 l'diiodoundecane' The reaction leading to the compounds of Formula I 10 Llz'dnodododecane to the invention can be typified by the following equation: The following compounds are respectively obtained:

Example Compound 2 CHz-SOz-CHz-SOr-O-(CH:r-OSO:CHa-SO:CH; 136-139 3.- CHz-SOr-CHz-SOz-O-(CH: .--oso,-cH=-so=-oHi 132-135 4-. CHg-SO:-CHz-SOz-O-(CH:5O-SOr-CHr-SO:CHI 101-106 5-- CHr-SOz-CHz-SOz-O-(CH: O-SOz-CHz-SO:CH 103-106 6-. CHz-SO1-CHzSO:O-(CH2)1-O-S0zCHa-SOr-CH: 75-90 7-. CHrSOr-CHg-SOr-O-(CH: r-O--SOz-CH2-SOzCH3 64-68 8-. CHz-SOz-CHrSOrO-(CH: oOSO CH:SOr-CH: 103-105 9 CHs-SOg-CH SOr-0-(CH1)n0SOzOHr-S0r-CH: -77 10 CHg-SO:CH2S0:O--(CHQIF'O' SOrCHrSOrCH; 109-111 As already mentioned, the new compoundsshow goodcytostatic activity.

The activity of the compounds according to the invention can be conveniently observed in the model of transplanted lymphatic leukemia L 1210 on mice as follows:

Mice weighing 18-22 g. (strain B 6 D 2 F 1) were injected intraperitoneally 2X10 leukemia cells (L 1210) in 0.2 mol of ascites fluid.

The treatment was carried out 4 times, on successive days, by intraperitoneal administration, and started 24 hours after the transplantation of the leukemia cells.

The duration of the test was 2-3 weeks.

To assess the results of the test, the survival time index (ST index) was determined as-follows:

If the survival time 50 of the control group is treated as 100%, it is possible, using the formula ST 50 of the treated groupX 100 ST 1ndex= ST 50 f the ontrol group to compute a quotient which can betreated as an index of the change in the ST under the treatment.

Assessment: Values 100% denote a reduced survival time of the treated group of animals and hence a toxic action of the preparation.

Values l00% denote an increased survival time 50, which, depending on the level of the index, express an inhibition of the tumor growth.

The results are shown in Table 1.

l In mgJkg. of body weight, 4X intraperitoneally. I The compound of the formula CHs-b0;0-(CH:)4-O-S O2-CH4, from British Pat. No. 700,677, served as the comparison substance.

The new compounds are preferably administered orally and can be used either as such or in combination with non-toxic, inert, pharmaceutically tolerated excipients. Suitable forms for administration, in combination with various inert excipients, are tablets, dragees, capsules, granules, aqueous suspensions and emulsions, non-aqueous emulsions and suspensions, syrups and the like. Such excipients include solid diluents or fillers, aqueous media, as well as various non-toxic organic diluents and the like. Of course, tablets and the like can be provided with a sweetener and similar substances. The therapeutically active compound should, in the above mentioned case, be present in a concentration of about 0.5 to 90 percent by weight of the total mixture, in amounts which sufiice to achieve dosage range which is cytostatically effective.

The formulations are manufactured according to conventional techniques, for example by extending the active substances with diluents and/ or excipients, optionally using emulsifiers and/or dispersing agents, such as water, non-toxic organic solvents or diluents, such as parafiins, vegetable oils, such as groundnut oil and sesame oil, alcohols, such as ethyl alcohol or glycerol, glycols, such as propylene glycol or polyethylene glycol, solid excipients, such as, for example natural rock powders for example kaolins, aluminas, talc or chalk, synthetic rock powders, such as highly disperse silica and silicates, sugars as for example unrefined sugar, lactose and glucose; smulsifiers, such as non-ionic and anionic emulsifiers as for example polyoxyethylene-fatty acid esters, polyoxyethylene-fatty alcohol ethers, alkylsulfonates and arylsulfonates, dispersing agents, such as lignin, sulfite waste lycs, methylcellulose, starch and polyvinylpyrrolidone and lubricants, such as magnesium stearate, talc, stearic acid and sodium lauryl sulfate.

Apart from the excipients mentioned, tablets can of course also contain additives, such as sodium citrate, calcium carbonate and dicalcium phosphate, together with various further substances such as starch, preferably potato starch, gelatin and the like. Furthermore, lubricants such as magnesium stearate, sodium lauryl sulfate and talc can additionally be used for making tablets. In the case of suspensions and emulsions, the active substances can be mixed with various flavor improving agents or dyestuffs in addition to the above mentioned auxiliaries.

The active substances can also be contained in the form of dosage units in capsules, tablets, pastilles, dragees, ampoules and the like, each dosage unit being so adapted as to yield a single. dose of the active constituent.

The new compounds can also be present in the formulations as mixtures with other known active substances.

In general it has proved advantageous to administer amounts of about 5 mg. to 50 mg./kg. of body weight per day to achieve cytostatically effective results. Nevertheless it will at times be necessary to deviate from the amounts mentioned, and in particular to do so as a function of the body weight of the test animal, the method of administration, the type of animal and its individual behavior towards the cytostatic agent, the type of formulation, and the administration regimen. Thus it will in some cases suffice to use less than the above mentioned minimum, while in others the upper limit mentioned must be exceeded. Where larger amounts are administered, it can be advisable to divide these into several individual administrations over the course of the day.

What is claimed is:

1. A compound of the formula:

wherein n has a value of from 1 to 14.

2. A compound according to claim 1, wherein n has a 'value of from 3 to 12.

3. The compound according to claim 1, wherein n is 8, said compound is of the formula:

4. The compound according to claim 1, wherein n is 3-,- said compound is of the formula:

5. The compound according to claim 1, wherein n is 4, said compound is of the formula:

5 6 6. The compound according to claim 1, wherein n is References Cited 6, said compound is of the formula: FOREIGN PATENTS CH SO -CH S0 -O-(CH 705,892 3/1965 Canada 260-456 OSO -CH SO C'H 5 700,677 12/ 1953 Great Britain 260-456 OTHER REFERENCES Chem. Abstracts 64: 5970 (1966). CH SO -CH z 2)'r- Chem. Abstracts 49: 45580 (1955).

O-SO CH SO CI-I 7. The compound according to claim 1, wherein n is d d t 1 1 h 10 BERNARD HELFIN, Primary Examiner er 1S gfi ijfigfifig jfifi ff g ifi W m n N. MORGENSTERN, Assistant Examiner 

